The concurrent existence of cancer with specific neurologic disorders, known as paraneoplastic syndromes, often requires extensive or invasive studies or is established at autopsy. Paraneoplastic symptoms usually precede the detection of the cancer, may affect any part of the nervous system, and are often more debilitating than the cancer itself. Paraneoplastic limbic encephalitis (PLE) is one of these syndromes, initially recognized in 1968 (Corsellis, J. A. N. et al., Brain 91:481-496 (1968)). The presenting symptoms of PLE are irritability, depression, seizures, severe memory deficit and dementia. These symptoms correlate with the areas of the nervous system with major pathological involvement (hippocampus, amygdala, hypothalamus, and insular and cingulate cortices) but most studies also show brainstem encephalitis (BE) and abnormalities in other areas that may or may not be clinically silent (Bakheit, A. M. O. et al, J. Neurol. Neurosurg. Psychiatry 53:1084-1088 (1990); Henson, R. A. and Urich, H., Cancer and the Nervous System, Blackwell Scientific Publications, Oxford, USA, 1989, pp. 314-345).
Due to the diversity of clinical symptoms and the frequent absence of specific markers, PLE is likely underdiagnosed. In patients with known cancer, symptoms of PLE can be attributed to other complications, including metastases to the brain, toxic and metabolic encephalopathy, infections, and side effects of cancer therapy. In about 60% of the patients, PLE precedes the detection of the tumor, complicating even more its clinical recognition (Dalmau, J. et al, Medicine 71:59-72 (1992); Alamowitch, S. et al., Brain 120:923-928 (1997)). The finding of abnormalities involving the mesial temporal lobes on MRI studies may raise the suspicion of PLE, but does not establish the diagnosis.
Some paraneoplastic syndromes affecting the nervous system are associated with antibodies that react with neuronal proteins and the causal tumor (onconeuronal antigens) (Greenlee, J. E. , Ann. Neurol 12:102 (1982); Graus, F. et al., Neurology 35:538-543 (1985); Budde-Steffen, C. et al., Ann. Neurol. 23:528-531 (1988); Dalmau, J., and Posner, J. B., Semin. Oncol. 24:318-328 (1997)). Several of these antibodies are markers of specific neurologic syndromes associated with distinct types of cancer (Furneaux, H. M. et al., New Engl. J. Med. 322:1844-1851 (1990); Luque, F. A. et al., Ann. Neurol. 29:241-251 (1991); Dalmau, J. et al., Medicine 71:59-72 (1992)). The presence of some antibodies is so specific that disorders previously identified by brain biopsy, or at autopsy, can now be diagnosed serologically (Henson, R. A. et al., Brain 88:449-464 (1965); Anderson, N. E. et al., Ann. Neurol. 24:559-567 (1988); Dalnau, J. et al., Ann. Neurol. 27:544-552 (1990); Posner, J. B. (ed.), Paraneoplastic Syndromes. Neurologic Complications of Cancer, Philadelphia, FA Davis Company, pp. 353-385 (1995)). The expression of neuronal proteins by the tumor is probably a crucial step that breaks immune tolerance for otherwise normal neuronal proteins (Carpentier et al. Neurology 50:A354-355 (1998)).
To date, characteristic antineuronal antibodies have been discovered in only a few paraneoplastic disorders. Because of debilitating nature of paraneoplastic syndromes, as well as the diversity of clinical symptoms and the frequent absence of specific markers, it is critical to identify new means for diagnosing paraneoplastic syndromes.
The current invention pertains to isolated Ma family proteins, particularly Ma1 (SEQ ID NO:4), Ma2 (SEQ ID NO:7), Ma3 (SEQ ID NO:9), Ma4 (SEQ ID NO:11) and Ma5 (SEQ ID NO:13), as well as active or functional derivatives or fragments of the Ma family polypeptides. The invention also pertains to nucleic acids encoding Ma family polypeptides, as well as nucleic acid constructs comprising the nucleic acid molecules described herein operatively linked to a regulatory sequence, and to recombinant host cells comprising the nucleic acid molecules described herein operatively linked to a regulatory sequence. The invention also pertains to isolated antibodies, or antigen-binding fragments thereof, which selectively bind to Ma family polypeptides or active derivatives or fragments thereof.
The invention further pertains to methods of diagnosing a paraneoplastic syndrome in an individual, by assessing a test sample (e.g., of bodily fluid or tissue, or of antibodies isolated from a bodily fluid or tissue), for the presence, absence, or amount of antibodies that bind to a Ma family polypeptide such as Ma1 and/or Ma2. The presence of antibodies that bind to a Ma family polypeptide is indicative of the presence of a paraneoplastic syndrome; the absence of antibodies that bind to a Ma family polypeptide is indicative of the absence of a paraneoplastic syndrome. The invention additionally pertains to methods of diagnosing a neoplasm in an individual, by assessing a test sample (e.g., of bodily fluid or tissue, or of antibodies isolated from a bodily fluid or tissue), for the presence, absence, or amount of antibodies that bind to a Ma family polypeptide such as Ma1 and/or Ma2. The presence of antibodies that bind to a Ma family polypeptide is indicative of the presence of a neoplasm; the absence of antibodies that bind to a Ma family polypeptide is indicative of the absence of a neoplasm.